Process of synthesis of 5-methoxy- 2-[(4-methoxy-3,5-dimethy-2-pyridyl)methyl]sulfiny-1h-benzimidazole

a technology of methylsulfinyl and benzimidazole, which is applied in the direction of carbonyl group formation/introduction, functional group formation/introduction, digestive system, etc., can solve the problem of risk of contamination of the final product with heavy metals, the ph of the aqueous phase over the reaction mixture has to be carefully monitored

Inactive Publication Date: 2001-07-31
LEK TOVARNA FARM & KEMICNIH IZDELKOV D D
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A disadvantage of the said process is also the fact that the pH of the aqueous phase over the reaction mixture has to be carefully monitored during the whole process.
At a greater amount of the catalyst there is also a risk of contamination of the final product with heavy metals.

Method used

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  • Process of synthesis of 5-methoxy- 2-[(4-methoxy-3,5-dimethy-2-pyridyl)methyl]sulfiny-1h-benzimidazole
  • Process of synthesis of 5-methoxy- 2-[(4-methoxy-3,5-dimethy-2-pyridyl)methyl]sulfiny-1h-benzimidazole

Examples

Experimental program
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example 1

5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (10 g; 0.0304 mole) was suspended in ethyl acetate (100 ml) and cooled below 0.degree. C. 3-chloroperoxybenzoic acid (5.25 g; 0.0304 mole) was added in such a manner that the temperature did not exceed 5.degree. C. After completed addition it was left to crystallize for another half an hour at a temperature below 5.degree. C. The product formed was filtered off, washed with ethyl acetate and dried in vacuo. Crude omeprazole (8.3 g; 79.1%) was obtained.

Crude omeprazole (5 g) was dissolved in water (20 ml) and 40% aqueous methylamine (4 ml). The clear solution was diluted with acetone (30 ml) and the pH was adjusted to 7 to 8 with 1N HCl. To the suspension formed, water (70 ml) was added. The crystals separated were filtered off, washed with water and dried in vacuo. Pure omeprazole (4.6 g; 92%) was obtained.

example 2

5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (10 g; 0.0304 mole) was suspended in ethyl acetate (100 ml) and cooled below 0.degree. C. 3-chloroperoxybenzoic acid (5.25 g; 0.0304 mole) was added in such a manner that the temperature did not exceed 5.degree. C. After the completed addition it was stirred for half an hour, the cooling was removed, a 4% sodium carbonate solution (40 ml) was added and it was stirred for another half an hour. The product was filtered off and washed with water. After drying in vacuo crude omeprazole (8.0 g; 76.2%) was obtained and it was purified according to the process disclosed in Example 1.

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Abstract

An improved process of synthesis of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl-1H-benzimidazole (omeprazole) by oxidation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole with 3-chloroperoxy-benzoic acid in ethyl acetate wherein omeprazole is poorly soluble, at a temperature between -10° C. and 5° C. is disclosed. The second step is a purification of the crude product by dissolution and reprecipitation of the final product.

Description

(C07D 401 / 12)The present invention relates to an improved process of synthesis of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl-1H-benzimidazole (omeprazole) of the formula ##STR1##wherein 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole is reacted with 3-chloroperoxybenzoic acid in ethyl acetate, wherein the final product--omeprazole--is poorly soluble.Omeprazole is the first medicament from the group of formulations for controlling the secretion of gastric acid, from the group of proton pump inhibitors. Namely, it inhibits the enzyme H / K-ATPase (a proton pump) in a parietal cell and thus also inhibits the last phase of acid secretion.TECHNICAL PROBLEMThere is a constant need to prepare omeprazole of high purity in a simple and readily feasible way. In the literature processes of synthesis up to a crude omeprazole are disclosed; said omeprazole, however, contains by-products and hence it is not suitable for pharmaceutical use.PRIOR ART5-met...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07B41/00C07B41/06C07D401/12C07D401/00A61K31/00A61P1/00C07D213/00C07D235/00
CPCC07D401/12C07B41/06A61P1/00A61P1/04
Inventor MILAC, NATASA HAFNERJEREB, DARJA
Owner LEK TOVARNA FARM & KEMICNIH IZDELKOV D D
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